Lawrence D. Longo

The biological effects of carbon monoxide on the pregnant woman, fetus, and newborn infant

Abstract Significant alterations of a number of physiologic functions result from relatively low blood carboxyhemoglobin concentrations. Pregnant women, fetuses, and newborn infants are particularly susceptible to carbon monoxide effects. This paper reviews the physiologic and biochemical bases of these effects and their clinical implications.

Mercury toxicity in the pregnant woman, fetus, and newborn infant. A review

This paper reviews the reported cases of mercury poisoning in pregnancy and the data based on sources of contamination, maternal uptake, and distribution. It analyzes current knowledge of placental transfer of various mercury compounds, fetal uptake, and distribution. It identifies the embryopathic and fetal toxic effects of mercury in general while emphasizing the greater toxicity of methylmercury compounds. Since maternal exposure to methylmercury is primarily through fish consumption, it recommends that women of childbearing age should not consume more than 350 Gm. of fish per week. In addition, they should not be occupationally exposed to air concentrations of mercury vapor greater than 0.01 mg. per cubic meter, of inorganic and phenylmercuric compounds greater than 0.02 mg. per cubic meter, or any detectable concentration of methylmercury.

Regional Cerebral Blood Flow: Studies in the Fetal Lamb during Hypoxia, Hypercapnia, Addosis, and Hypotension

ABSTRACT: In order to determine the relative roles of O2 tension and content, CO2 tension, hydrogen ion concentration, arterial blood pressure, and cardiac output in the regulation of fetal cerebral blood flow (CBF), we used radioactively labeled microspheres to measure flow to 20 major brain regions in 24 chronically catheterized fetal lambs. We continually monitored fetal heart rate and blood pressure, and periodically measured arterial Po2, Pco2, pH, and hematocrit. In addition to CBF measurements during control periods, we measured CBF during: 1) hypoxia (O2 content < 6 ml·dl-1; O2 tension < 15 torr) induced by having the ewe breathe a gas mixture with low O2 concentration, 2) hypercapnia (Pco2 > 50 torr) induced by increasing the maternal inspired CO2, 3) acidosis and alkalosis (7.60 > pH > 6.60) induced by infusing lactic acid or bicarbonate into the fetus, and 4) hypotension (blood pressure < 35 mm Hg) and hypertension (blood pressure > 55 mm Hg) induced by rapidly phlebotomizing or transfusing the fetus. We used multiple regression analysis and analysis of covariance to examine the dependence of total cerebral blood flow on arterial O2 tension and content, CO2 tension, pH, blood pressure, and cardiac output. The results demonstrated that 1) fetal CBF increased linearly as oxygen tension or content decreased and a hierarchy of responsivity occurred (brainstem > subcortex and cortex), 2) fetal CBF increased as carbon dioxide tension increased with a different hierarchy of responsivity (brainstem > subcortex > cortex), and 3) autoregulation of fetal CBF over a wide range of blood pressure or cardiac output was maintained for both total CBF and the various brain regions examined.

Brain Renin-Angiotensin System: Fetal Epigenetic Programming by Maternal Protein Restriction During Pregnancy

Objective: Maternal protein malnutrition during pregnancy can lead to significant alterations in the systemic renin-angiotensin system (RAS) in the fetus. All components of the RAS are present in brain and may be altered in many disease states. Importantly, these disorders are reported to be of higher incidence in prenatally malnourished individuals. In the current study, we tested the hypothesis that antenatal maternal low protein diet (MLPD) leads to epigenetic changes and alterations in gene expression of brain RAS of the mouse fetus. Methods: Mice dams were given control and 50% MLPD during second half of the gestation. We analyzed messenger RNA (mRNA), microRNA (miRNA), promoter DNA methylation, and protein expression of various RAS genes in the fetal offspring. Results: As a consequence of 50% MLPD, fetal brains showed increased mRNA expression of angiotensinogen and angiotensin converting enzyme-1 (ACE-1), with a decrease in mRNA levels of angiotensin II type-2 (AT2) receptors. In contrast, while angiotensinogen protein expression was unaltered, the protein levels of ACE-1 and AT2 receptor genes were significantly reduced in the fetal brain from the MLPD dams. Our results also demonstrated hypomethylation of the CpG islands in the promoter regions of ACE-1 gene, and upregulation of the miRNAs, mmu-mir-27a and 27b, which regulate ACE-1 mRNA translation. Furthermore, our study showed reduced expression of the miRNA mmu-mir-330, which putatively regulates AT2 translation. Conclusion: For the developing fetal brain RAS, MLPD leads to significant alterations in the mRNA and protein expression, with changes in DNA methylation and miRNA, key regulators of hypertension in adults.

Gene expression in the placenta: maternal stress and epigenetic responses

Successful placental development is crucial for optimal growth, development, maturation and survival of the embryo/fetus into adulthood. Numerous epidemiologic and experimental studies have demonstrated the profound influence of intrauterine environment on life, and the diseases to which one is subject as an adult. For the most part, these invidious influences, whether maternal hypoxia, protein or caloric deficiency or excess, and others, represent types of maternal stress. In the present review, we examine certain aspects of gene expression in the placenta as a consequence of maternal stressors. To examine these issues in a controlled manner, and in a species in which the genome has been sequenced, most of these reported studies have been performed in the mouse. Although each individual maternal stress is characterized by up- or down-regulation of specific genes in the placenta, functional analysis reveals some patterns of gene expression common to the several forms of stress. Of critical importance, these genes include those involved in DNA methylation and histone modification, cell cycle regulation, and related global pathways of great relevance to epigenesis and the developmental origins of adult health and disease.

Prenatal Gender-Related Nicotine Exposure Increases Blood Pressure Response to Angiotensin II in Adult Offspring

Epidemiological studies suggest that maternal cigarette smoking is associated with an increased risk of elevated blood pressure (BP) in postnatal life. The present study tested the hypothesis that prenatal nicotine exposure causes an increase in BP response to angiotensin II (Ang II) in adult offspring. Nicotine was administered to pregnant rats via subcutaneous osmotic minipumps throughout the gestation. BP and vascular responses to Ang II were measured in 5-month–old adult offspring. Prenatal nicotine had no effect on baseline BP but significantly increased Ang II–stimulated BP in male but not female offspring. The baroreflex sensitivity was significantly decreased in both male and female offspring. Prenatal nicotine significantly increased arterial media thickness in male but not female offspring. In male offspring, nicotine exposure significantly increased Ang II–induced contractions of aortas and mesenteric arteries. These responses were not affected by inhibition of endothelial NO synthase activity. Losartan blocked Ang II–induced contractions in both control and nicotine-treated animals. In contrast, PD123319 had no effect on Ang II–induced contractions in control but inhibited them in nicotine-treated animals. Nicotine significantly increased Ang II type 1 receptor but decreased Ang II type 2 receptor protein levels, resulting in a significant increase in the ratio of Ang II type 1 receptor/Ang II type 2 receptor in the aorta. Furthermore, the increased contractions of mesenteric arteries were mediated by increases in intracellular Ca2+ concentrations and Ca2+ sensitivity. These results suggest that prenatal nicotine exposure alters vascular function via changes in Ang II receptor–mediated signaling pathways in adult offspring in a gender-specific manner, which may lead to an increased risk of hypertension in male offspring.

Placental anatomy and diffusing capacity in guinea pigs following long-term maternal hypoxia

To determine the relation of placental structure to placental diffusing capacity (DPCO), we exposed Hartley guinea pigs to 12 or 14 per cent O2 from day 15 of gestation to near term (64 days). At that time we measured DPCO and fetal body and placental weights. In addition, we used stereological techniques to measure placental parameters important to diffusing capacity. We also used a mathematical model with results from the stereological measurements to predict the diffusing capacity. In the first hypoxic group (E1), measured DPCO decreased 10.1 +/- 3.7 per cent, while that predicted was 2.4 per cent less than control. Total vascular volume decreased 6.6 +/- 3.6 per cent, while tissue volume and mean diffusion distance increased 10.2 +/- 5.6 per cent and 12.9 +/- 7.0 per cent, respectively. In the pair-fed animals, measured DPCO decreased 22.6 +/- 4.6 per cent, while that predicted was 20.0 per cent less than control. There were no significant stereological differences in this group. In the second (E2) hypoxic group, measured DPCO increased 27.2 +/- 7.4 per cent, while that predicted increased 38.2 per cent. For this same group, total vascular volume increased 11.7 +/- 3.0 per cent, and tissue volume and mean diffusion distance decreased 18.2 +/- 4.6 per cent and 17.8 +/- 3.8 per cent, respectively. These results demonstrate the dependence of placental diffusing capacity upon placental structure.

Exercise guidelines in pregnancy: new perspectives.

In 2002, the American College of Obstetricians and Gynecologists published exercise guidelines for pregnancy, which suggested that in the absence of medical or obstetric complications, 30 minutes or more of moderate exercise a day on most, if not all, days of the week is recommended for pregnant women. However, these guidelines did not define ‘moderate intensity’ or the specific amount of weekly caloric expenditure from physical activity required. Recent research has determined that increasing physical activity energy expenditure to a minimum of 16 metabolic equivalent task (MET) hours per week, or preferably 28 MET hours per week, and increasing exercise intensity to ≥60% of heart rate reserve during pregnancy, reduces the risk of gestational diabetes mellitus and perhaps hypertensive disorders of pregnancy (i.e. gestational hypertension and pre-eclampsia) compared with less vigorous exercise. To achieve the target expenditure of 28 MET hours per week, one could walk at 3.2km per hour for 11.2 hours per week (2.5 METs, light intensity), or preferably exercise on a stationary bicycle for 4.7 hours per week (~6–7 METs, vigorous intensity). The more vigorous the exercise, the less total time of exercise is required per week, resulting in ≥60% reduction in total exercise time compared with light intensity exercise. Light muscle strengthening performed over the second and third trimester of pregnancy has minimal effects on a newborn infant’s body size and overall health. On the basis of this and other information, updated recommendations for exercise in pregnancy are suggested.

Behavioral sequelae in young rats of acute intermittent antenatal hypoxia

Several studies have examined behavioral sequelae of acute or chronic pre- or postnatal hypoxia. However, few of these tested a large battery of behavioral functions, particularly those following relatively mild, intermittent hypoxia. Also, in few studies were the hypoxic pups cross-fostered or the experimenter blinded as to experimental group. In addition, in almost no studies were concomitant hypoxic-induced brain biochemicals measured. The present study tested the hypotheses that mild, intermittent antenatal hypoxia can lead to long-term alterations in neurobehavioral development, as well as neurochemical changes.

Ovine Placentome Morphology: Effect of High Altitude, Long-term Hypoxia

The effect of high altitude, long-term hypoxaemia on placentome morphology in the sheep was examined using singleton and twin pregnant ewes. Normoxic twins had lower fetal and placental weights (3.7+/-0.2 kg and 215+/-26 g, respectively) than normoxic singleton fetuses (4.3+/-0.2 kg and 336+/-17 g, respectively). Fetal and placental weights were similar in normoxic singleton and high altitude (3820 m) hypoxic singleton fetuses (4.3+/-0.2 and 4.4+/-0.4 kg, 336+/-17 and 342+/-62 g, respectively). The distribution of placentome types was classified into four major categories (A-D) and for normoxic singletons was as follows: A=76+/-4, B=22+/-3, C=1+/-2, and D=1+/-1. Normoxic twins tended to have more type B (type A=63+/-10, B=33+/-8, C=2+/-1, and D=2+/-1). High altitude hypoxic singletons had significantly fewer type A (33+/-4) and more type B (50+/-3), C (10+/-7), D (7+/-1) placentomes than normoxic singletons. In addition, in the sea-level control group, five animals were found to be spontaneously hypoxic with a placentome distribution similar to that of the high altitude hypoxic fetuses. In conclusion, both high altitude, long-term hypoxia and low altitude spontaneous hypoxia lead to a significant change in placentome distribution with less type A and increases in types B, C and D. Physiologically, the change in the several placentome types with high altitude hypoxia suggests an acclimatization response to optimize transplacental exchange efficiency.